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Endothelium-targeting nanoparticle for reversing endothelial dysfunction

a technology of endothelium and nanoparticles, applied in the direction of biocide, antibody medical ingredients, genetic material ingredients, etc., can solve the problem of not providing the required expression levels, and achieve the effect of promoting the long-term production of gtpch proteins

Inactive Publication Date: 2005-03-10
TEXAS A&M UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0006] The present invention includes a polymerized nanoparticle with a targeting ligand that is prepared and used to deliver an isolated and purified nucleic acid sequence encoding a GTP cyclohydrolase (GTPCH) polypeptide to damaged endothelial cells. The delivery of the GTPCH nucleic acid promotes long-term production of the GTPCH protein in endothelial cells of individuals with either type I (insulin-dependent) or the more prevalent type II (insulin-resistant) diabetes. The delivery system can be used to treat endothelial damage caused by diabetes, smoking, dyslipidemia, hypertension, and / or cardiovascular disease.

Problems solved by technology

Currently available delivery systems, e.g., viral vectors, fail to provide the required expression levels, specificity of localization and have caused some safety concerns for use in humans.

Method used

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  • Endothelium-targeting nanoparticle for reversing endothelial dysfunction
  • Endothelium-targeting nanoparticle for reversing endothelial dysfunction
  • Endothelium-targeting nanoparticle for reversing endothelial dysfunction

Examples

Experimental program
Comparison scheme
Effect test

example i

Nitric Oxide (NO) Synthesis in Endothelial Cells is Impaired in Diabetes

[0058] As shown herein, the inhibition of NO synthesis in the spontaneously diabetic BB (BBd) rat is due to decreased levels of tetrahydrobiopterin (BH4), secondary to decreased expression of GTP cyclohydrolase I (GTPCH). In one example, an adenoviral GTPCH gene transfer was used to reverse BH4 deficiency and repair the ability of endothelial cells to produce NO. GTPCH gene transfer increased BH4 levels in BBd endothelial cells from 0.17±0.02 (mean±SEM) to 73.37±14.42 pmoles / million cells and NO production from 0.77±0.07 to 18.74±5.52 nmole / 24 hr / million cells.

[0059] To demonstrate a functional effect of increasing BH4 concentrations in tissues, GTPCH was transferred into aortic rings from BBd and Zucker diabetic fatty (ZDF) rats, models of human type I and type II diabetes, respectively. GTPCH gene transfer led to a dose-dependent increase in acetylcholine-induced vasorelaxation, preventable by inhibiting NO ...

example 2

Design and Use of a Nanoparticle to Improve Endothelial Cell Function

[0091] A targeting nanoparticle complex may be prepared containing a condensed DNA core (containing a nucleic acid sequence encoding GTPCH), a hydrophobic polymer layer, a hydrophilic polymer layer, and a layer of ligand at the outer surface (Lox-1 receptor monoclonal antibody). These nanoparticles are designed to deliver the nucleic acid sequence to damaged endothelial cells, increasing tetrahydrobiopterin and nitric oxide synthesis in these dysfunctional cells. By increasing production of GTPCH protein, and thus tetrahydrobiopterin and nitric oxide synthesis in cells, the impairment in the cell can be reversed or reduced, and endothelial function will be improved. In addition, by increasing the cellular level of tetrahydrobiopterin in the cell, the antioxidant pool is increased and the cell will be protected from future oxidative damage.

example 3

Assembly of a Nanoparticle Complex

[0092] The assembled nanoparticle complex can have a layered structure with a condensed DNA core, a hydrophobic polymer layer, a hydrophilic polymer layer and a layer of ligand at the outer surface. This layered nanoparticle will be generated by the self assembly of DNA on mixing with a tripartite polymer conjugate. This tripartite polymer conjugate will include a DNA binding cationic polymer such as polyethyleneimine (PEI), a hydrophilic polymer polyethylene glycol (PEG) covalently conjugated to primary amines of PEI, and a ligand (e.g., Lox-1 monoclonal antibody [Lox-1-mAb]) conjugated to the distal end of PEG. On mixing with DNA, PEI will bind and condense the plasmid DNA forming a hydrophobic core and the hydrophilic PEG polymer will form a layer around the core providing a steric protective coat. Since the ligand is attached to the end of PEG, it will be exposed on the surface of the resulting nanoparticle (50-100 nm in size). While the steric...

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Abstract

The present invention includes delivery of isolated and purified nucleic acids that encode GTPCH proteins in nanoparticles for the treatment of endothelial cells damaged by diabetes, smoking, dyslipidemia, hypertension, and cardiovascular disease. The nanoparticles contain a nucleic acid sequence, polymer and a targeting ligand. The targeting ligand facilitates the selective delivery of the nucleic acid sequence to damaged endothelial cells. Examples involving a nucleic acid sequence encoding GTP-cyclohydrolase I (GTPCH), PEG / PEI polymers, and a monoclonal antibody or other molecule that binds to the lectin-like oxidized low density lipoprotein (LDL) receptor-1 (Lox-1) or associated molecules are presented.

Description

TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to compositions and methods for the delivery of nucleic acids to endothelial cells and, more specifically, to nanoparticle-mediated delivery of nucleic acids to damaged blood vessels in individuals with cardiovascular disease resulting from diabetes, hypertension, dyslipidemia, and / or smoking. DESCRIPTION OF RELATED ART [0002] This application claims priority to U.S. Provisional Patent Application Ser. No. 60 / 481,336, filed Sep. 5, 2003. Without limiting the scope of the invention, its background is described in connection with diabetes, hypertension, dyslipidemia and smoking. [0003] Diabetes is one of the most prevalent and costly chronic diseases in the U.S. According to the Centers for Disease Control and Prevention, one in three Americans born in the year 2000 will develop diabetes. The prevalence is even higher for Hispanics where the estimated lifetime risk is 45% for males and 53% for females. One in ten he...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K48/00C12N15/85
CPCA61K9/5146A61K48/005A61K48/0008
Inventor MEININGER, CYNTHIA J.
Owner TEXAS A&M UNIVERSITY
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